Claims:

1. A process of preparing a beta-amido carbonyl compound of formula XXX:
##STR00363## comprising the steps of:a) reacting a compound of formula
XII: ##STR00364## with a compound of formula XIII: ##STR00365## in the
presence of a palladium catalyst, a palladium ligand, a base, and a
solvent optionally including a phase transfer catalyst and optionally
including water,to produce a compound of the formula XXXI ##STR00366##
wherein:X is a leaving group;Each Ra is H, an optionally substituted
alkyl, an optionally substituted aryl, --CN, --C(O)-- Oalkyl or
halogen;Each R2 is independently an optionally substituted aliphatic
group, an optionally substituted heterocyclic group, and an optionally
substituted aryl group;Each R4 is independently an optionally
substituted aliphatic, an optionally substituted heterocycle, an
optionally substituted aryl, or R2 and R1 together with the
groups to which they are bound, form an optionally substituted 5- to
8-membered heterocyclic ring; andEach R3 is an organic moiety.

2. The process of claim 1, wherein the palladium catalyst is Pd(OAc)2
or Pd2 dba.sub.3.

5. The process of claim 1, wherein the solvent is toluene, dioxane, THF,
or a mixture thereof.

6. The process of claim 1, wherein the base is K2CO3 or
Cs2CO.sub.3.

7. The process of claim 1, wherein the reaction mixture includes a phase
transfer catalyst and optionally water.

8. The process of claim 1, wherein the palladium catalyst is Pd(OAc)2
or Pd2 dba3; the palladium ligand is phosphine, bisphosphine,
XantPhos, DPEPhos, or bis(diphenylphosphino) ferrocene; the solvent is
toluene, dioxane, THF, or a mixture thereof; and the base is
K2CO3 or Cs2CO.sub.3.

9. The process of claim 1, wherein R3 is an optionally substituted
aliphatic, an optionally substituted aryl, an optionally substituted
heteroalkyl, an optionally substituted heteroaryl, a protecting group,
P2--, P3--P2--, or P4--P3--P2--;P2--
is ##STR00367## P3--P2 is ##STR00368##
P4--P3--P2 is ##STR00369## T is --C(O)--, --O--C(O)--,
--NHC(O)--, --C(O)C(O)-- or --SO2--;Each R is independently an
optionally substituted aliphatic, or an optionally substituted aryl;Each
R5 is independently H, an optionally substituted aliphatic, an
optionally substituted heteroalkyl, an optionally substituted heteroaryl,
or an optionally substituted phenyl;Each R6 is independently an
optionally substituted aliphatic, an optionally substituted heteroalkyl,
an optionally substituted heteroaryl, an optionally substituted phenyl,
or R5 and R6 taken together with the atoms to which they are
attached form a 5 to 7 membered, optionally substituted monocyclic
heterocycle, or a 6 to 12 membered, optionally substituted bicyclic
heterocycle, in which each heterocycle ring optionally contains an
additional heteroatom selected from --O--, --S-- or --NR50--;
andEach R7 is independently H, an optionally substituted aliphatic,
an optionally substituted heteroalkyl, an optionally substituted
heteroaryl, or an optionally substituted phenyl, orR7 and R6
together with the atoms to which they are attached form a 5 to 7
membered, optionally substituted monocyclic heterocycle, a 5 to 7
membered, optionally substituted monocyclic aryl, a 6 to 12 membered,
optionally substituted bicyclic heterocycle, or a 6 to 12 membered,
optionally substituted bicyclic aryl, in which each heterocycle or aryl
ring optionally contains an additional heteroatom selected from --O--,
--S-- or --NR50--, orwhen R5 and R6 together to with the
atoms to which they are attached form a ring, R7 and the ring system
formed by R5 and R6 form a 8- to 14-membered optionally
substituted bicyclic fused ring system, wherein the bicyclic fused ring
system is optionally further fused with an optionally substituted phenyl
to form an optionally substituted 10- to 16-membered tricyclic fused ring
system;Each R8 is independently H or a protecting group; andEach
R50 is independently H, an optionally substituted aliphatic, an
optionally substituted heteroalkyl, an optionally substituted heteroaryl,
or an optionally substituted phenyl; andm is 0 to 2.

11. The process of claim 1 further comprising reducing the compound of
formula XXXI to produce a compound of Formula XXX.

12. The process of claim 11, wherein R4 and R2 taken together
with the atoms to which they are attached form a substituted
beta-amidolactone of the formula ##STR00370## wherein R9 is
C1-C5 alkyl. ##STR00371##

13. The process of claim 1, wherein R3 has the structure in which
each R5 is independently H, an optionally substituted aliphatic, an
optionally substituted heteroalkyl, an optionally substituted heteroaryl,
or an optionally substituted phenyl;each R6 is independently an
optionally substituted aliphatic, an optionally substituted heteroalkyl,
an optionally substituted heteroaryl, an optionally substituted phenyl,
or R5 and R6 taken together with the atoms to which they are
attached form a 5 to 7 membered, optionally substituted monocyclic
heterocycle, or a 6 to 12 membered, optionally substituted bicyclic
heterocycle, in which each heterocycle ring optionally contains an
additional heteroatom selected from --O--, --S-- or --NR50--;Each
R8 is independently H or a protecting group;Each R50 is
independently H, an optionally substituted aliphatic, an optionally
substituted heteroalkyl, an optionally substituted heteroaryl, or an
optionally substituted phenylm is 0 to 2.

14. The process of claim 13, wherein R3 has the structure
##STR00372## in which Ring A is a 5 to 7 membered, optionally substituted
monocyclic heterocycle, or a 6 to 12 membered, optionally substituted
bicyclic heterocycle, in which each heterocycle ring optionally contains
an additional heteroatom selected from --)--, --S-- or --NR.sub.50--.

15. The process of claim 14, wherein Ring A has the structure:
##STR00373##

16. The process of claim 15, wherein R3 has the structure
##STR00374##

17. The process of claim 14, wherein R3 has the structure
##STR00375##

18. The process of claim 17, wherein R3 has the structure
##STR00376##

19. The process of claim 17, wherein the compound of formula XII has the
structure ##STR00377## in which R9 is C1-C5 alkyl, and the
compound of formula XXXI has the structure ##STR00378##

20. The process of claim 19, wherein R9 is --CH2CH.sub.3.

21. The process of claim 20, wherein R8 is a protecting group.

22. The process of claim 20, wherein the protecting group is CBZ.

23. A process of producing a compound of ##STR00379## comprising purifying
a mixture of ##STR00380## wherein R8 is a protecting group, and
purifying includes chromatographing, selectively crystallizing, or
dynamically crystallizing the mixture.

24. The process of claim 23, wherein the step of purifying the mixture
comprises separating the isomers by chromatography.

25. The process of claim 23, wherein the step of purifying the mixture
comprises selectively crystallizing the mixture with an organic solvent.

26. The process of claim 23, wherein the step of purifying comprises
dynamic crystallization which comprises contacting the mixture with a
lewis acid and a solvent optionally including a protic acid.

27. The process of claim 26, wherein the step of purifying comprises
contacting the mixture with Al(Oalkyl)3 in a solvent under acidic
conditions.

28. The process of claim 27, wherein the mixture is epimerized with
Al(OEt)3 in toluene in the presence of HCl.

29-52. (canceled)

53. The process of claim 1, wherein the reaction between the compound of
formula XII and the compound of formula XIII is carried out optionally in
the presence of an ammonium bromide.

54. The process of claim 53, wherein the reactions between the compound of
formula XII and the compound of formula XIII is carried out in the
presence of an ammonium bromide.

55. The process of claim 54, wherein the ammonium bromide is
cetyltrimethylammonium bromide.

Description:

[0002]Caspases are a family of cysteine protease enzymes that are key
mediators in the signaling pathways for apoptosis and cell disassembly
(Thornberry, Chem. Biol., 1998, 5, R97-R103). Apoptosis, or programmed
cell death, is a principal mechanism by which organisms eliminate
unwanted cells. The deregulation of apoptosis, either excessive apoptosis
or the failure to undergo it, has been implicated in a number of diseases
such as cancer, acute inflammatory and autoimmune disorders, and certain
neurodegenerative disorders (see generally Science, 1998, 281, 1283-1312;
Ellis et al., Ann. Rev. Cell. Biol., 1991, 7, 663). Caspase-1, the first
identified caspase, is also known as interleukin-1β converting
enzyme or "ICE." Caspase-1 converts precursor interleukin-1β
("pIL-1β") to the pro-inflammatory active form by specific cleavage
of pIL-1β between Asp-116 and Ala-117. Besides caspase-1 there are
also eleven other known human caspases which have been classified into
families based on their biological function.

[0003]A number of useful caspase inhibitors have been reported that
contain an aspartic acid aldehyde moiety, which will exist in equilibrium
with its cyclic hemiacetal form as shown below:

##STR00001##

where W2 represents the rest of the caspase inhibitor molecule. Based
on the hemiacetal, orally available prodrugs of these inhibitors have
been developed having the acetal structure 1, including the compound 2 in
which R1 is alkyl. The ICE inhibitor 2 is a prodrug being developed
as a treatment for rheumatoid arthritis (see U.S. Pat. No. 5,716,929).

[0005]It would be desirable to have a synthetic route to aspartic acetal
caspase inhibitors, or prodrugs thereof, that is amenable to large-scale
synthesis and overcomes the aforementioned shortcomings or otherwise
improves upon the current methods.

[0012]R2 is an optionally substituted alkyl, heterocyclic, alkylaryl,
or aryl; and

[0013]R4 is an optionally substituted aliphatic, a heterocyclic, or
an aromatic; or

[0014]R2 and R4 together with the groups to which they are
bound, form a 5- to 8-membered heterocyclic ring which is optionally
substituted. Embodiments of this aspect may include using a phase
transfer catalyst.

[0015]Other aspects of the invention are set forth herein.

DESCRIPTION OF THE INVENTION

I. Definitions

[0016]As used herein, the base used in connection with palladium catalyst
and palladium ligand refers to an "inorganic base" or an "organic base".

[0017]As used herein, "inorganic bases" that may be used in a process of
this invention include, but are not limited to a carbonate salt, a
bicarbonate salt, and/or a phosphate salt (and mixtures thereof). In some
embodiments of this invention, the inorganic base may be a carbonate salt
having the formula MCO3, wherein M is an appropriate counter-cation.
Examples of carbonate salts include, but are not limited to,
K2CO3, K2PO4, Na2CO3, Li2CO3,
Rb2CO3, and Cs2CO3. In some specific embodiments, the
inorganic base is K2CO3 or Cs2CO3.

[0018]As used herein, "organic bases" that may be used in a process of
this invention include tertiary organic bases that include, but are not
limited to trialkylamines, e.g. diethylisopropylamine, triethylamine,
N-methylmorpholine and the like, and heteroaryl amines, e.g. pyridine,
quinoline, and the like.

[0019]As used herein, "Palladium catalysts" that may be used in a process
of this invention include, but are not limited to, Palladium II Salts
such as Pd(OAc)2 and Pd2 dba3.

[0020]As used herein, "Palladium ligand" and "Palladium II Ligand" refers
to a ligand that is capable of forming a complex with the palladium
catalyst. Palladium ligands include, but are not limited to, phosphine,
bisphosphine, XantPhos, bis(diphenylphosphino)ferrocene and DPEPhos (see
Aldrich catalog). See also, WO 95/30680 and U.S. Pat. No. 5,817,848.

[0021]"Solvents" for use in this invention include, but are not limited
to, toluene, dioxane, and THF, and mixtures thereof.

[0022]The term "leaving group" refers to a moiety which is replaced by
R3CONH2. Specific groups include, but are not limited to,
chloro, bromo, iodo, pseudohalogens, triflate, tosylate, mesylate, and
nosylate.

[0023]The term "organic moiety" as used in defining variable R3
refers to any chemical moiety provided that the moiety does not contain a
moiety that would interfere with the palladium catalysts. Such
interfering moieties would be well known to skilled practitioners and
include, e.g., a free sulfhydryl group. A group such as a sulfide or a
thiol should not therefore be present in the R3 organic moiety.
Furthermore, the R3 organic moiety should not contain an amine
group, such as a primary or secondary amine that would be more reactive
than the amide of formula (GIIA or GIIB). R3 may contain primary and
secondary amines that are capped with protecting groups that reduce the
interaction between the protected amine and the palladium catalysts.

[0024]As used herein, the term "phase transfer catalyst" means a compound
which is capable of transferring a water soluble anion into an organic
phase. Phase transfer catalysts include tetralkylammonium salts,
phosphonium salts and crown ethers. Examples of phase transfer catalysts
include, but are not limited to tetrasubstituted ammonium salts and
trisubstituted amines which may form tetrasubstituted ammonium salts in
situ. Tetrasubstituted ammonium salts include, but are not limited to,
tetrabutylammonium, benzyltrimethylammonium, tetraethylammonium,
cetyltrimethylammonium salts in which the counter ion can be salts
bromide, chloride, or iodide. In some examples, the phase transfer
catalyst is cetyltrimethylammonium bromide. Trisubstituted amines
include, but are not limited to triethylamine, tributylamine,
benzyldiethylamine, and diisopropylethylamine.

[0025]As used herein, the terms "lactone" and "furanone" may be used
interchangeably as will be understood by one skilled in the art.

[0026]As used herein, the term "aliphatic" means straight chained,
branched or cyclic C1-C12 hydrocarbons which are completely
saturated or which contain one or more units of unsaturation. For
example, suitable aliphatic groups include substituted or unsubstituted
linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids
thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or
(cycloalkyl)alkenyl.

[0027]The term "alkyl" and "alkoxy" used alone or as part of a larger
moiety refers to both straight and branched chains containing one to
twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as
part of a larger moiety shall include both straight and branched chains
containing two to twelve carbon atoms.

[0028]As used herein, the term "aryl", used alone or as part of a larger
moiety as in "aralkyl", refers to aromatic ring groups having five to
fourteen members, such as phenyl, benzyl, 1-naphthyl, 2-naphthyl,
1-anthracyl and 2-anthracyl, and heterocyclic aromatic groups or
heteroaryl groups such as 2-furanyl, 3-furanyl, N-imidazolyl,
2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, a 1,3,4-oxadiazolyl, a 1,2,4-oxadiazolyl, 2-oxadiazolyl,
5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl,
3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,
5-pyrimidyl, 3-pyridazinyl, 2-thiadiazolyl, 5-thiadiazolyl, 2-thiazolyl,
4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl,
2-thienyl, or 3-thienyl. The term "aryl ring" also refers to rings that
are optionally substituted. Aryl groups also include fused polycyclic
aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl
ring is fused to one or more other rings. Examples include
tetrahydronaphthyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl,
quinolinyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl,
isoindolyl, acridinyl, benzoisoxazolyl, and the like. Also included
within the scope of the term "aryl", as it is used herein, is a group in
which one or more carbocyclic aromatic rings and/or heteroaryl rings are
fused to a cycloalkyl or non-aromatic heterocyclic ring, for example,
indanyl or tetrahydrobenzopyranyl. The term "aromatic ring" or "aromatic
group" refers to aryl groups.

[0029]The term "heterocyclic" refers to saturated and partially
unsaturated monocyclic or polycyclic ring systems containing one or more
heteroatoms and a ring size of three to eight such as piperidinyl,
piperazinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
morpholinyl, and the like.

[0030]As used herein, the term "bicyclic fused ring system" or "bicyclic
ring system" refers to two rings which share two atoms. Either ring may
be saturated, partially unsaturated, or aromatic. Each ring also may
contain 1 to 3 heteroatoms. Examples of bicyclic fused ring systems
include, but are not limited to, compounds g, j, k, l, and m shown in
Table 1, and compounds g-1 and j-1, l-1, l-2, k-1, m-1 and m-2 shown in
Table 2.

[0031]As used herein, the term "tricyclic fused ring system" or "tricyclic
ring system" refers to a bicyclic ring system in which a third ring is
fused to the bicyclic ring system such that the third ring shares at
least two atoms with the bicyclic ring system. In some embodiments, all
three rings share at least one common atom. Any of the rings in the
tricyclic ring system may be saturated, partically unsaturated, or
aromatic. Each of the rings may include 1 to 3 heteroatoms. Examples of
tricyclic ring systems include, but are not limited to, compounds e and q
shown in Table 1, and compounds e-1 and q-1 shown in Table 2.

[0032]As used herein, the phrase "optionally substituted" followed by a
chemical moiety (e.g., an optionally substituted aliphatic) means that
the chemical moiety may be substituted with one or more (e.g., 1-4)
substituents. In some embodiments, aliphatic groups, alkyl groups, aryl
groups, heterocyclic groups, carbocyclic groups, and bicyclic or
tricyclic ring systems contain one or more substituents. The substituents
are selected from those that will be stable under the reaction conditions
of the present process, as would be generally known to those skilled in
the art. Examples of substituents include halogen, -Q1, --OQ1,
--OH, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, --OPh,
substituted --OPh, --NO2, --CN, --NHQ1, --N(Q1)2,
--NHCOQ1, --NHCONHQ1, --NQ1CONHQ1,
--NHCON(Q1)2, --NQ1CON(Q1)2,
--NQ1COQ1, --NHCO2Q1, --NQ1CO2Q1,
--COQ1, --CONQ1, --CON(Q1)2, --S(O)2Q1,
--SONH2, --S(O)Q1, --SO2NHQ1,
--SO2N(Q1)2, --NHS(O)2Q1,
--NQ1S(O)2Q1, ═O, ═S, ═NNHQ1,
═NN(Q1)2, ═N--OQ1, ═NNHCOQ1,
═NNQ1COQ1, ═NNHCO2Q1,
═NNQ1CO2Q1, ═NNHSO2Q1,
═NNQ1SO2Q1, or ═NQ1 where Q1 is an
optionally substituted aliphatic, aryl or aralkyl group.

[0033]As used herein, nitrogen atoms on a heterocyclic ring may be
optionally substituted. Suitable substituents on the nitrogen atom
include Q2, COQ2, S(O)2Q2, and CO2Q2, where
Q2 is an aliphatic group or a substituted aliphatic group.

[0034]Unless otherwise stated, structures depicted herein are also meant
to include all stereochemical forms of the structure; i.e., the R and S
configurations for each asymmetric center. Therefore, single
stereochemical isomers as well as enantiomeric and diastereomeric
mixtures of the present compounds are within the scope of the invention.

[0035]The term "substantially pure" refers to the stereochemical purity of
a compound that is greater than 90%. In some embodiments, the
stereochemical purity of a compound is greater than 95%. And in still
others, the stereochemical purity of a compound is 99% or greater.

[0036]The term "selective crystallization" means crystallization of a
substantially pure isomer from a solvent containing a mixture of isomers.

[0037]The term "dynamic crystallization" means crystallization of a
substantially pure isomer from a solvent containing a mixture of isomers
under conditions which cause isomerization of the mixture of isomers to
an isomer which selectively crystallizes. For example, in the case of
resolving enantiomers, isomerization of the more soluble enantiomer to
the less soluble isomer results in crystallization of the less soluble
isomer as the equilibrium between the isomers is driven by
crystallization toward the less soluble enantiomer. A specific example of
dynamic crystallization may include the epimerization of an anomeric
carbon in a solvent under conditions which selectively crystallizes one
substantially pure enantiomer.

[0038]Unless otherwise stated, structures depicted herein are also meant
to include compounds which differ only in the presence of one or more
isotopically enriched atoms. For example, compounds having the present
structures except for the replacement of a hydrogen by a deuterium or
tritium, or the replacement of a carbon by a 13C- or
14C-enriched carbon are within the scope of this invention.

[0043]The general synthetic procedure shown in Scheme 1 is useful for
generating a wide array of chemical species which can be used in the
manufacture of pharmaceutical compounds.

##STR00006##

The process shown in Scheme 1 includes reacting a compound of formula GII
with the amide GIII in the presence of a palladium catalyst, a palladium
ligand and a base in a solvent optionally including a phase transfer
catalyst and optionally including water to produce the amido carbonyl
compound GI.

[0044]The moietys X, Ra, R2, R3 and R4 are defined
above. As drawn, GII refers to compounds in which X may be cis or trans
to Ra, which provides for both the cis and trans compounds of GI, e.g.,
R2 can be cis or trans to Ra.

[0045]In some embodiments, the process may be used to prepare a compound
of formula XIV, when the moietys R2 and R4 shown in Scheme I
form a substituted heterocyclic ring:

##STR00007##

wherein R3 and Ra are defined above and R5 is an optionally
substituted aliphatic, optionally substituted aralkyl, optionally
substituted heterocyclylalkyl or optionally substituted aryl.
Specifically, compound XIV may be produced by reacting a compound of
formula XV:

##STR00008##

and a compound of formula XIII:

##STR00009##

in the presence of a palladium catalyst, a palladium II ligand, a base, a
solvent, and optionally a phase transfer catalyst; wherein X, R3,
and R5 are defined above.

[0046]In carrying out the reaction shown in Scheme 1, the reactants and
reagents may be used in any molar amount which provides the desired
product. In some embodiments, the ratio of the molar amounts of palladium
II salt to palladium ligand is between 1:1 to about 1:5. The ratio of the
molar amounts of palladium II salt to the reactant GIII can be between
about 1:200 to about 1:1, about 1:100 to about 1:25, or about 1:50 to
about 1:10. The ratio of the molar amount of the base relative to the
GIII is between about 1:2 to about 10:1. The two reactants, GII and GIII,
and the base can be used in nearly equal molar amounts. In some
embodiments, the ratio of GII and GIII can be between about 1:3 to about
3:1.

[0047]The reaction in Scheme I may be conducted at a temperature between
25° C. and 120° C., e.g., about 50° C., in any
solvent that does not adversely interfere with the palladium catalyst,
the palladium ligand, and the reactants. Examples of suitable solvents
are described herein and can include toluene, dioxane, THF, and mixtures
thereof. In some embodiments, the solvent may include water.

[0048]After obtaining the compound XIV, the compound of formula XVI:

##STR00010##

may be obtained by reducing the furanone ring double bond.

[0049]The reduction of a furanone ring double bond may be accomplished
with a hydride reducing agent, especially a borohydride. Examples of such
borohydrides include sodium or lithium borohydride, sodium or lithium
triacetoxyborohydride, sodium or lithium cyanoborohydride,
tetrabutylammonium cyanoborohydride, sodium or lithium
trialkylborohydride, preferably sodium cyanoborohydride. Typically the
reaction mixture is adjusted to be mildly acidic, preferably at a pH
between 3.0 and 6.0 with acids such as HCl, HBr, acetic acid, formic
acid, trifluoroacetic acid, BF3.OEt2, aluminum trichloride,
zinc chloride, or titanium tetrachloride. Optionally, the reaction may be
buffered with 1.0-5.0 equivalents of sodium acetate. Optionally, the
reaction may be catalyzed by the addition of 1-5% CoCl2/semicorrin,
ZnCl2, or 1-2 equivalents of chlorotrimethylsilane. Chiral hydride
reducing agents are known such as R- or S-Alpine Hydride® (lithium
B-isopinocampheyl-9-bora-bicyclo[3.3.1]nonyl hydride) to provide
asymmetric reduction.

[0050]Reduction of the ring double bond in, e.g., XIV may also be
accomplished by hydrogenation. This is useful when R5 is stable to
the hydrogenation conditions, such as when R5 is alkyl. Typical
hydrogenation conditions include hydrogen gas at a pressure in the range
of about one to 100 atmospheres, usually between about 1 to about 20, or
about 1 to about 10 atmospheres, and a catalyst present in the range of
about 0.01 to 0.5 equivalents per equivalent of XIV (for example).
Suitable catalysts include Pd/C, Pd(OH)2, PdO, Pt/C, PtO2,
preferentially Pt/C or Pd/C. Suitable solvents include ethyl acetate,
alcohols, such as methanol, ethanol, isopropanol, aromatic hydrocarbons,
such as benzene, toluene, xylene, ethereal such as THF, DME, dioxane,
preferentially ethanol or THF. When R5 is alkyl or aralkyl, such as
benzyl, a rhodium (I) or ruthenium (II) catalyst is preferred for
stereoselective reduction. Such catalyst is formed by reacting the metal
as one of its various complexes with chiral forms of ligands such as
methyl- or ethyl-DuPHOS (1,1-bis-2,5-dialkylphospholano)benzene, DIOP
(2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane),
BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), CHIRAPHOS
(bis(diphenylphosphino)butane), BPPM
(N-t-butoxycarbonyl-2-(diphenylphosphino)methyl-4-(diphenylphosphino)pyrr-
olidine), BPPFA (N,N-dimethyl-1-[1',2-bis(diphenylphosphino)
ferrocenyl]ethylamine), DEGPHOS
(N-benzyl-3,4-bis(diphenylphosphino)pyrrolidine), or alkyl-BPE
(bisphospholanoethane). Many other suitable ligands are known in the art.
Preferred catalysts are 1,2-bis(2,5-dialkyl-phospholano)benzene
(cyclooctadiene)rhodium(I) trifluoromethanesulfonate, where alkyl is a
straight chain or branched alkyl group of 1-8 carbons, optionally
substituted with an aromatic hydrocarbon such as phenyl.

[0052]In certain embodiments, when the moiety R3 includes a chiral
carbon bound to the carbonyl of the amide, GIII has the stereochemistry
shown in

##STR00011##

as for example in the structure GIV'

##STR00012##

The reaction of GIV provides the compound of the formula

##STR00013##

[0053]The stereoisomers of GV may be purified by selective
crystallization, dynamic crystallization or chromatography.

[0054]As described herein, R3 is any organic moiety. Specifically, it
will be understood that the R3 group may be selected from any
organic moiety that is stable to conditions of the coupling reaction
shown in Scheme I, such as those conditions described herein.

[0055]In specific embodiments, the general process shown in Scheme 1 is
useful for producing caspase inhibitors, such as prodrugs of caspase
inhibitors, e.g., ICE inhibitors, and intermediates thereof. In these
embodiments, R3 is preferably any moiety that, taken as a whole with
the rest of the molecule, provides such an inhibitor. Typically, for
caspase inhibitors, the R3 moiety is specifically referred to in the
art as a P2, P3, P4, or combination thereof, moiety or
site. Examples of P2, P3, P4 moieties are describe in more
detail below.

[0056]The Px moiety terms refer to the amino acid sequence next to
the aspartyl cleavage site of a particular caspase substrate. P1
refers to the aspartyl residue of the substrate where caspase-induced
cleavage occurs in the natural substrate. In the design of new,
nonpeptidic caspase inhibitors, the Px designation is often retained
to show which portion of the amino acid sequence has been replaced by the
non-peptidic moiety. As used herein, the term "P2-P4" moiety
refers to either the amino acid sequence described above or a chemical
moiety known to replace such a sequence for the purpose of being a
caspase substrate, and in particular an ICE substrate.

[0058]As would be recognized by skilled practitioners, a P moiety is not
necessarily an amino acid residue. For example, a P4 group could be
referred to as an amino capping group (e.g., phenyl-C(O)--). Such P4
groups are exemplified herein.

[0059]In another embodiment, this invention provides a process for
preparing a compound of formula XVI:

##STR00014##

wherein R3 is a P4--P3--P2 moiety of a caspase
inhibitor, or portion thereof. Each P2, P3, and P4 group
may be incorporated into XVI either individually or together. For
example, if R3 is a group other than a P2 group (e.g., a
protecting), the R3C═O group may be removed to provide a
compound with a free amine group. That amine group and an appropriate
P2 moiety may be coupled under, e.g., standard coupling conditions
to provide a compound wherein R3 is a P2 moiety of a caspase
inhibitor. A P3 and a P4 group may be added together or
individually in a similar manner. For example, if the P2 moiety is
protected, the protecting group may be removed and a P3 or a
P4--P3-- moiety (optionally protected) may be incorporated. If
a capping group other than a typical protecting group is desired on any
of the terminal P2, P3, or P4 residues, such a group may
be added routinely by methods known to skilled practitioners.

[0060]Accordingly, one embodiment provides a process wherein R3 is a
P2-- moiety of a caspase inhibitor.

[0061]Another embodiment provides a process wherein R3 is a
P3--P2-- moiety of a caspase inhibitor.

[0062]Yet another embodiment provides a process wherein R3 is a
P4--P3--P2-- moiety of a caspase inhibitor.

[0063]Another embodiment provides a process wherein R3 is a
P4--P3--P2-- moiety of a caspase inhibitor, and wherein
said moiety is one of the groups listed in Table 1 below; or wherein said
moiety is one of the groups listed in Table 2 below.

[0064]According to another embodiment, R3 is a
P4--P3--P2-- moiety wherein the P4 portion thereof is
selected from R--CO, ROC═O, RNHC═O, RC(O)C═O or RSO2 and
R is one of the groups listed in Table 3.

[0065]According to yet another embodiment, R3 is a
P4--P3--P2-- moiety selected from one of the groups listed
in Table 4.

[0068]In a specific embodiment, the invention provides a process for
preparing a compound of formula I:

##STR00015##

comprising:

[0069](a) reacting a compound of formula II:

##STR00016##

and a compound of formula III:

##STR00017##

in the presence of a palladium catalyst, a palladium ligand, a base,
optionally a phase transfer catalyst and a solvent to provide the
compound of formula I.

[0070]According to another embodiment, this invention provides a process
for preparing a compound of formula IV:

##STR00018##

comprising reducing and deprotecting a compound of formula I:

##STR00019##

to provide a compound of formula V:

##STR00020##

reacting the compound of formula V with cbz-tert-leucine, under
appropriate coupling conditions, to provide a compound of formula VI:

##STR00021##

reacting the compound of formula VI under conditions for removing the cbz
group; appropriate conditions would be those that provide an amine (or
amine salt) (i.e., under conditions for deprotecting the cbz-protected
amine of the tert-leucine, such as, e.g., H2 Pd/C, citrate acid
((CO2H)2)); after deprotection the resultant amine is reacted
with 4-amino-3-chlorobenzoic, or a derivative thereof that is suitable
for coupling to an amine (e.g., 4-amino-3-chlorobenzoyl chloride), under
appropriate coupling conditions, to provide the compound of formula IV.

[0071]According to another embodiment, the invention provides a process
for preparing a compound of formula IV:

##STR00022##

comprising reacting a compound of formula I:

##STR00023##

under deprotection conditions, that is, under conditions suitable to
remove the cbz group of the proline residue, to provide a compound of
formula VII:

##STR00024##

reacting the compound of formula VII with cbz-tert-leucine, under
appropriate coupling conditions, to provide a compound of formula VIII:

##STR00025##

reducing and deprotecting the compound of formula VIII to provide a
compound of formula IX:

##STR00026##

reacting a compound of formula IX and 4-amino-3-chlorobenzoic acid, or a
derivative thereof that is suitable for coupling to an amine (e.g., the
4,6-dimethoxy-2-hydroxypyrazine ester of 4-amino-3-chlorobenzoic acid),
under appropriate coupling conditions, to provide the compound of formula
IV.

[0072]This invention also provides a compound of formula X, wherein the
compound is prepared according to the methods herein:

##STR00027##

wherein:

[0073]R5 is an optionally substituted group selected from an
aliphatic group, aralkyl group, heterocyclylalkyl group or aryl group;
and

[0074]R6 is H or an amine capping group.

[0075]The processes described herein are useful for producing a of formula
I:

##STR00028##

[0076]The process may also be used to produce substantially pure,
diastereomers of compound I shown as formulae IA, IB, IC, and ID.

##STR00029##

[0077]Scheme 1 may also produce a mixture of diastereomers IA and IC:

##STR00030##

[0078]According to another embodiment, this invention provides a process
for preparing a compound of formula IA:

##STR00031##

[0079]comprising the step of selectively crystallizing a compound of
formula:

##STR00032##

from toluene.

[0080]This selective crystallization step comprises combining the compound
of formula IA/C (i.e., a mixture of IA and IC) and toluene (either at
room temperature or above) and warming the combination with stirring to
dissolve the compound of formula IA/C and cooling the combination with
stirring. Upon cooling, the compound of formula IA is obtained as a
crystalline solid (about 96:4 to about 97:3 mixture).

[0081]According still to another embodiment, this invention provides a
process for preparing a compound of formula IA:

##STR00033##

[0082]comprising the step of dynamic crystallization of a compound of
formula:

##STR00034##

under in the presence of a Lewis acid and a solvent, optionally including
a protic acid. In certain embodiments, the dynamic crystallization is
performed with Al(Oalkyl)3 in toluene. In other embodiments, dynamic
crystallization is performed with a lewis acid in a solvent containing a
protic acid such as HCl, HBr, triflic acid, sulfuric acid, phosphoric
acid, or combinations thereof.

[0083]In still other embodiments, the isomers IA and IC may be purified
and isolated by known chromatographic methods.

[0084]In any of the embodiments of this invention involving a compound of
formula I, one form of I is represented by the structure:

##STR00035##

[0085]In any of the embodiments of this invention involving a compound of
formula II, one form of II is represented by the structure:

##STR00036##

[0086]In any of the embodiments of this invention involving a compound of
formula III, one form of III is represented by the structure:

##STR00037##

[0087]In any of the embodiments of this invention involving a compound of
formula IV, one form of IV is represented by the structure:

##STR00038##

[0088]In any of the embodiments of this invention involving a compound of
formula V, one form of V is represented by the structure:

##STR00039##

[0089]In any of the embodiments of this invention involving a compound of
formula VI, one form of VI is represented by the structure:

##STR00040##

[0090]In any of the embodiments of this invention involving a compound of
formula VII, one form of VII is represented by structure:

##STR00041##

[0091]In any of the embodiments of this invention involving a compound of
formula VIII, one form of VIII is represented by structure:

##STR00042##

[0092]In any of the embodiments of this invention involving a compound of
formula IX, one form of IX is represented by structure:

##STR00043##

[0093]Also provided are compounds formula XA, XB, XC, or XD, wherein the
compound is prepared according to the methods herein:

##STR00044##

wherein:

[0094]R5 is optionally substituted aliphatic, aralkyl, or aryl; and

[0095]R6 is H or an amine capping group.

[0096]In one embodiment, R5 is an optionally substituted group
selected from an aliphatic group, aralkyl group, heterocyclylalkyl group
and an aryl group.

[0098]In another embodiment, R5 is ethyl or an optionally substituted
benzyl.

[0099]In yet another embodiment, R5 is ethyl or benzyl.

[0100]In one embodiment of this invention, R6 is an amine capping
group and the amine capping group is --C(O)R7 or --C(O)OR7, and
the R7 is (C6-C10)-aryl- or (C6-C10)-aryl-(C1-C12)aliphatic-,
wherein the aryl is optionally substituted. In one form of this
embodiment, --C(O)OR7, wherein R7 is optionally substituted
benzyl, preferably benzyl.

[0101]Any amines obtained as described herein, may be used with or without
isolation from the reaction mixture. The desired caspase inhibitor
prodrug may be derived from, e.g., V, VII, or the free amine of XIV
(either as depicted or in the reduced form) by attaching the appropriate
P2. P2--P3, or P2--P3--P4 moiety. A
coupling of an amine with such a moiety may be carried out using the
corresponding carboxylic acid, or reactive equivalent thereof, under
standard amide bond-forming or coupling conditions. A typical coupling
reaction includes a suitable solvent, the amine in a concentration
ranging from about 0.01 to 10M, preferably about 0.1 to 1.0M, the
requisite carboxylic acid, a base and a peptide coupling reagent.

[0102]If an amine is used without isolation, the coupling may be carried
out in situ in the solvent of the reaction mixture used in the
preparation of the amine, or in a different solvent. To this reaction
mixture, the requisite carboxylic acid may be added and the reaction
maintained at a temperature in the range of about 0° to
100° C., preferably between about 20° to about 40°
C. The base and peptide coupling reagent are then added to the mixture,
which is maintained at a temperature in the range of about 0° to
about 60° C., preferably between about 20° to about
40° C. The base is typically a tertiary amine base, such as
triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN,
N-methylimidazole, preferably triethylamine or diisopropylethylamine. The
amount of base used is generally up to about 20 equivalents per
equivalent of the amine (e.g., IV), preferably at least about 3
equivalents of base. Examples of peptide coupling reagents include DCC
(dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide),
di-p-toluoylcarbodiimide, BDP (1-benzotriazole
diethylphosphate-1-cyclohexyl-3-(2-morpholinylethyl)carbodiimide), EDC
(1-(3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride), cyanuric
fluoride, cyanuric chloride, TFFH (tetramethyl fluoroformamidinium
hexafluorophosphosphate), DPPA (diphenylphosphorazidate), BOP
(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate),
HBTU (O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate), TBTU
(O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate),
TSTU (O--(N-succinimidyl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate), HATU
(N-[(dimethylamino)-1-H-1,2,3-triazolo[4,5,6]-pyridin-1-ylmethylene]-N-me-
thylmethanaminium hexafluorophosphate N-oxide), BOP-Cl
(bis(2-oxo-3-oxazolidinyl)phosphinic chloride), PyBOP
((1-H-1,2,3-benzotriazol-1-yloxy)-tris(pyrrolidino)phosphonium
tetrafluorophopsphate), BrOP (bromotris(dimethylamino)phosphonium
hexafluorophosphate), DEPBT
(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) PyBrOP
(bromotris(pyrrolidino)phosphonium hexafluorophosphate). EDC, HOAT,
BOP-Cl and PyBrOP are preferred peptide coupling reagents. The amount of
peptide coupling reagent is in the range of about 1.0 to about 10.0
equivalents. Optional reagents that may be used in the amide bond-forming
reaction include DMAP (4-dimethylaminopyridine) or active ester reagents,
such as HOBT (1-hydroxybenzotriazole), HOAT (hydroxyazabenzotriazole),
HOSu (hydroxysuccinimide), HONB
(endo-N-hydroxy-5-norbornene-2,3-dicarboxamide), in amounts ranging from
about 1.0 to about 10.0 equivalents.

[0103]Alternatively, one may treat an amine with a reactive equivalent of
the R3COOH carboxylic acid, such as P2--, P3--P2--,
or P4--P3--P2--C(═O)X1, where C(═O)X1 is
a group that is more reactive than COOH in the coupling reaction.
Examples of --C(═O)X1 groups include groups where X1 is Cl,
F, OC(═O)R (R=aliphatic or aryl), SH, SR, SAr, or SeAr.

[0104]A number of chemical groups are known that may be used as the
P3--P2-- portion of the ICE or caspase inhibitor prodrug.
Examples of such P3--P2-- groups are shown in Table 1 as part
of a P4--P3--P2-- moiety.

[0108]In specific embodiments, R-T- is R--CO where R is 1-naphthyl,
2-naphthyl, 1-isoquinolinyl, or

##STR00153##

where positions 3 and 5 of R are independently and optionally substituted
by halogen, preferably chloro, or C1-3 alkyl, and position 4 is
optionally substituted by amino, acetamido, hydroxy or methoxy.

[0111]In attaching the P4--P3--P2-- moiety, or portion
thereof, the moiety may be attached in one piece as or subunits of the
moiety may be added in a sequential manner as described above. For
example, Cbz-protected proline may be coupled to XV (or if R5 is
ethyl with II):

##STR00164##

[0112]After removal of the Cbz group, a P3 or P3--P4 moiety
may be attached by alkylation or acylation of the proline nitrogen.

[0113]In certain embodiments, methods of the present process proceed
through the butenolactone XV where X is chloro, bromo or iodo:

##STR00165##

A preferred starting butenolactone is the bromofuranone XV (wherein
X═Br), which may be obtained according to Escobar et al., An. Quim.,
1971, 67, 43. Alternatively, other reactants of the formula GIIA and GIIB
may be commercially available or produced from know methods. See, for
example, "Comprehensive Organic Transformations: A Guide to Functional
Group Preparations," 2nd Edition, by Richard C. Larock, pages 638, 659,
661, 724.

[0114]Also within the scope of this invention, another embodiment of the
coupling reaction of an amine proceeds by acylation of the anion of the
amine using a reactive equivalent of the carboxylic acid, such as
P2--, P2--P3--, or
P2--P3--P4--C(═O)X1, where C(═O)X1 is as
described above. The anion of the amine is first generated by treating
the amine in a solvent with any suitable base. Examples of solvents that
may be used include ethereal solvents such as THF, DME, dioxane, diethyl
ether, methyl-tert-butyl ether; aromatic hydrocarbons, such as benzene,
toluene, xylene; halogenated hydrocarbons, such as dichloromethane,
carbon tetrachloride, dichloroethane; or other organic solvents, such as
acetonitrile. Preferred solvents include THF, DME, toluene or
dichloromethane. Suitable bases for generating the anion include organic
bases such as an alkali metal hydride, an alkali metal tert-butoxide, an
alkyl or aryl lithium, such as methyl-, butyl- or phenyllithium; an
alkali metal amide, such as lithium-, sodium- or potassium
bis(trimethylsilyl)amide, diisopropylamide, or tetramethylpiperidine.
Preferred bases include lithium bis(trimethylsilyl)amide, lithium
diisopropylamide, or lithium tetramethylpiperidine. The anion of the
amine is treated with the carboxylic acid equivalent at a reaction
temperature that may be in the range of about -78° C. to
120° C., preferably between about 0° C. to 60° C.

[0115]Reduction conditions for reducing the double bond in the furanone
ring may also be used as deprotection conditions. For example, when
R3 (in XIV) or R6 (in X) is cbz, conditions may be used to
reduce the double bond and to also remove the cbz group.

[0116]Methods herein describe a sequence in which the butenolactone is
first coupled to a caspase Px or Px-y moiety and then the ring
double bond is reduced. Alternatively, the reduction and coupling may be
performed in reverse order.

[0117]In still another embodiment, this invention provides a process for
preparing a compound of formula XVI:

##STR00166##

wherein R3 is a P4--P3--P2 moiety of a caspase
inhibitor, the P4--P3--P2 is c-1 of Table 2, the P4
is 108 of Table 3, R5 is as defined herein (e.g., ethyl) and the
process is according to the methods herein.

[0118]This invention also provides a process for preparing a compound of
formula IVA:

##STR00167##

comprising selective crystallization of a compound of formula:

##STR00168##

from toluene.

[0119]Alternatively, a process for preparing a compound of formula IVA:

##STR00169##

comprises dynamic crystallization of a compound of formula:

##STR00170##

by contacting the mixture of IA/C with a Lewis acid in a solvent
optionally including a protic acid.

[0120]This invention also provides a process for preparing a compound of
formula IVA:

##STR00171##

comprising, reacting a compound of formula II:

##STR00172##

and a compound of formula III:

##STR00173##

in the presence of a palladium catalyst, a palladium ligand, and a base in
a solvent optionally including a phase transfer catalyst.

[0121]Also provided are methods of preparing the corresponding aldehyde
compound (of e.g., XVI) by these processes. For example, compound IV
prepared according to this invention, may be converted to the
corresponding aldehyde compound, that is by converting the furanone to an
aldehyde.

[0122]In another embodiment, this invention provides a process for
preparing a compound of formula XVI:

##STR00174##

wherein R3 is a P4--P3--P2 moiety of a caspase
inhibitor, the P4--P3--P2 is d-1 of Table 2, P4 is
141 of Table 3, R5 is as defined herein (e.g., ethyl), and the
process is according to the methods herein.

[0123]Accordingly, this compound (see compound 412f and/or corresponding
compound 412 as disclosed in WO 97/22619, which is incorporated herein by
reference) is prepared by reacting a compound of formula II:

##STR00175##

and an appropriate amide compound, in the presence of a palladium
catalyst, a palladium ligand, a base, optionally a phase transfer
catalyst and an appropriate solvent. An appropriate amide compound would
be derived from the P4-P3-P2 group d-1a in Table 4, i.e., a compound:

##STR00176##

wherein R is either H or an isoquinolinoyl (i.e., the P4 group 141 in
Table 3, wherein there is a carbonyl linker between the compound and the
isoquinolinoyl group.

[0124]In still further embodiments, the invention provides a process of
preparing a beta-amido carbonyl compound of formula XXX:

##STR00177##

comprising the steps of:

[0125]a) reacting a compound of formula XII:

##STR00178##

with a compound of formula XIII:

##STR00179##

in the presence of a palladium catalyst, a palladium ligand, a base, in a
solvent optionally a phase transfer catalyst, to produce a compound of
the formula XXXI

[0129]Each R4 is independently an optionally substituted aliphatic,
an optionally substituted heterocycle, an optionally substituted aryl, or
R2 and R4 together with the groups to which they are bound,
form an optionally substituted 5- to 8-membered heterocyclic ring;

[0138]Each R6 is independently an optionally substituted aliphatic,
an optionally substituted heteroalkyl, an optionally substituted
heteroaryl, an optionally substituted phenyl, or R5 and R6
taken together with the atoms to which they are attached form a 5 to 7
membered, optionally substituted monocyclic heterocycle, or a 6 to 12
membered, optionally substituted bicyclic heterocycle, in which each
heterocycle ring optionally contains an additional heteroatom selected
from --O--, --S-- or --NR50;

[0139]Each R7 is independently H, an optionally substituted
aliphatic, an optionally substituted heteroalkyl, an optionally
substituted heteroaryl, or an optionally substituted phenyl, or
[0140]R7 and R6 together with the atoms to which they are
attached form a 5 to 7 membered, optionally substituted monocyclic
heterocycle or aryl (see, for example, compounds f, h, i, n, and o shown
in Table 1 and compounds o-1, o-2, and o-3 shown in Table 2), or a 6 to
12 membered, optionally substituted bicyclic fused ring system, in which
each of the fused rings optionally contains an additional heteroatom
selected from --O--, --S-- or --NR50-- (see, for example, compounds
g and j shown in Table 1, and compounds g-1 and j-1 shown in Table 2), or
[0141]when R5 and R6 together to with the atoms to which they
are attached form a ring, R7 and the ring system formed by R5
and R6 form a 8- to 14-membered optionally substituted bicyclic
fused ring system (see, for example, compounds g, k, l, and m, shown in
Table 1 and compounds d-1, d-2, k-1, l-1, l-2, m-1, and m-2 shown in
Table 2), wherein the bicyclic fused ring system is optionally further
fused with an optionally substituted phenyl to form an optionally
substituted 10- to 16-membered tricyclic fused ring system (see, for
example, compounds e and q shown in Table 1, and compounds e-1 and q-1
shown in Table 2);

[0142]Each R8 is independently H or a protecting group; and

[0143]Each R50 is independently H, an optionally substituted
aliphatic, an optionally substituted heteroalkyl, an optionally
substituted heteroaryl, or an optionally substituted phenyl; and

[0144]m is 0 to 2.

[0145]In some embodiments, R3 is an organic moiety.

[0146]In certain embodiments, the variable R in P4 may be an
aliphatic, aryl, or heteroaryl, each optionally substituted with 1 to 3
aliphatic, halo, alkoxy, --CN, --NO2, --N(R50)2,
--SOmN(R50)2, --NC(O)R50, --SOmR50 or
heterocycloalkyl.

[0147]The process further comprises reducing the compound of formula XXXI
to produce a compound of Formula XXX.

[0148]In some embodiments P2-- has the structure

##STR00184##

in which Ring A is a 5 to 7 membered, optionally substituted monocyclic
heterocycle, or a 6 to 12 membered, optionally substituted bicyclic
heterocycle, in which each heterocycle ring optionally contains an
additional heteroatom selected from --O--, --S-- or --NR50--,
R50 is H, an optionally substituted aliphatic, an optionally
substituted heteroalkyl, an optionally substituted heteroaryl, or an
optionally substituted phenyl.

[0149]In specific embodiments, Ring A has the structure:

##STR00185##

[0150]P2-- has the structure

##STR00186##

[0151]In certain embodiments, Ring A has the structure

##STR00187##

[0152]In specific embodiments P2-- has the structure

##STR00188##

[0153]In another embodiment, the a process for producing a compound of the
formula

##STR00189##

comprises:a) reacting a compound of the formula:

##STR00190##

with a compound of the formula:

##STR00191##

in the presence of a palladium catalyst, a palladium ligand, a base,
optionally a phase transfer catalyst and a solvent, to produce a compound
of the formula

[0157]Each R4 is independently an optionally substituted aliphatic,
an optionally substituted heterocycle, an optionally substituted aryl, or
R2 and R1 together with the groups to which they are bound,
form an optionally substituted 5- to 8-membered heterocyclic ring;

[0162]Each R6 is independently H, an optionally substituted
aliphatic, an optionally substituted heteroalkyl, an optionally
substituted heteroaryl, an optionally substituted phenyl, or R5 and
R6 taken together with the atoms to which they are attached form a 5
to 7 membered, optionally substituted monocyclic heterocycle, or a 6 to
12 membered, optionally substituted bicyclic heterocycle, in which each
heterocycle ring optionally contains an additional heteroatom selected
from --O--, --S-- or --NR7--;

[0174]Each R4 is independently an optionally substituted aliphatic,
an optionally substituted heterocycle, an optionally substituted aryl, or
R2 and R1 together with the groups to which they are bound,
form an optionally substituted 5- to 8-membered heterocyclic ring;

[0179]Each R6 is independently H, an optionally substituted
aliphatic, an optionally substituted heteroalkyl, an optionally
substituted heteroaryl, an optionally substituted phenyl, or R5 and
R6 taken together with the atoms to which they are attached form a 5
to 7 membered, optionally substituted monocyclic heterocycle, or a 6 to
12 membered, optionally substituted bicyclic heterocycle, in which each
heterocycle ring optionally contains an additional heteroatom selected
from --O--, --S-- or --NR50--;

comprises:a) contacting a racemic mixture of compounds represented by the
formula

##STR00206##

with a Lewis acid in an organic solvent optionally including a protic
acid, wherein

[0184]Ring A is a 5 to 7 membered, optionally substituted monocyclic
heterocycle, or a 6 to 12 membered, optionally substituted bicyclic
heterocycle, in which each heterocycle ring optionally contains an
additional heteroatom selected from --O--, --S-- or --NR50--;

[0185]Each R9 is a C1-C5 alkyl;

[0186]Each R10 is H, a protecting group, P3-- or
P4--P3--;

[0187]P3 is

##STR00207##

[0188]P4 is R-T;

[0189]T is --C(O)--, --O--C(O)--, --NHC(O)--, --C(O)C(O)-- or
--SO2--; and

[0190]Each R is independently an aliphatic, aryl, or a heteroaryl, each
optionally substituted with 1 to 3 aliphatic, halo, alkoxy,
--N(R50)2, --SOmN(R50)2, --NC(O)R50,
--SOmR50 or heterocycloalkyl;

[0191]Each R7 is independently H, an optionally substituted
aliphatic, an optionally substituted heteroalkyl, an optionally
substituted heteroaryl, or an optionally substituted phenyl, or
[0192]R7 and the Ring A form a 8- to 14-membered optionally
substituted bicyclic fused ring system, wherein the bicyclic fused ring
system is optionally further fused with an optionally substituted phenyl
to form an optionally substituted 10- to 16-membered tricyclic fused ring
system;

[0204]Each R7 is independently H, an optionally substituted
aliphatic, an optionally substituted heteroalkyl, an optionally
substituted heteroaryl, or an optionally substituted phenyl, or
[0205]R7 and the Ring A form a 8- to 14-membered optionally
substituted bicyclic fused ring system, wherein the bicyclic fused ring
system is optionally further fused with an optionally substituted phenyl
to form an optionally substituted 10- to 16-membered tricyclic fused ring
system;

[0210]In order that this invention be more fully understood, the following
preparative examples are set forth. These examples are for the purpose of
illustration only and are not to be construed as limiting the scope of
the invention in any way.

EXAMPLES

[0211]The abbreviations used herein are known to skilled practitioners.
Scheme 1 the syntheses that are exemplified below.

[0214]To a 1 L round bottom flask, CBZ-Pro-NH2 (20 g, 80.4 mmol),
Pd(OAc)2 (0.36 g, 1.6 mmol), XANTPHOS (1.4 g, 2.4 mmol) was charged.
The system was purged with nitrogen gas for 10 min. Toluene was added
(200 mL), and the reaction was stirred with warming to 50° C.
After reaching 50° C., the reaction was stirred for 30 min. The
mixture changed from a yellow slurry to a brick-red solution as the amide
dissolved and the (XANTPHOS)Pd(OAc)2 complex formed. A solution of
K2CO3 (26.6 g, 192 mmol) in water (200 mL) was added and the
reaction was allowed to warm to 50 C.

[0215]To a beaker, bromoethoxyfuranone (18.3 g, 88.4 mmol) and toluene (30
mL) was charged. The reaction is stirred until a solution is formed
(slight warming may be necessary because the dissolution is endothermic).
The solution of the bromide is added slowly to the catalyst/amide
solution at 50° C. over 3-3.5 hr. After the addition was complete,
stirring of the reaction mixture was continued at 50° C. for 4
hours. While still at 50° C., the phases were separated and the
aqueous phase discarded. The organic phase was washed with water (100 mL)
at 50° C. The phases were separated and the aqueous phase
discarded. The organic phase was concentrated to 1/2 volume and cooled to
ambient temperature. Seeds were added (50 mg) if crystallization has not
begun. The mixture was stirred at ambient temperature for 15 hr
(overnight), cooled to 0° C. and stirred for 3-5 hr. The solid was
filtered and rinsed with cold toluene. The solid was dried in vacuo at
40-50° C. to give a white crystalline solid (10.8 g, 36% yield).

[0217]Bromoethoxyfuranone (41.7 g, 201 mmol) as a solution in 30 mL
toluene was added to the brown/yellow mixture. The solution was warmed to
80° C. After 15 min, HPLC analysis showed 90% reaction complete
(comparing CBZ-proline amide and product), and no bromoethoxyfuranone
remained. Another 4.1 g of bromoethoxyfuranone was added to the reaction
mixture at 85° C. After stirring for 30 min, HPLC analysis showed
97% reaction completion. Another 2.8 g of bromoethoxyfuranone was added.
After stirring for 45 min, HPLC analysis showed no CBZ-proline amide
remaining. The mixture was cooled to 20-25° C., and water (200 mL)
was added, followed by saturated aqueous sodium hydrogen sulfate (400
mL). Gas evolution was observed. The phases were separated and the
organic phase was washed with saturated aqueous sodium hydrogen sulfate,
then water. The organic phase was dried over sodium sulfate, filtered,
and the solvent was removed in vacuo. The resulting crude material was
purified by flash chromatography (1:1 EtOAc:hexanes, then 3:1
EtOAc:hexanes) to give 55.7 g (74% yield) of the desired product as a
light brown oil.

[0220]To a flask was charged the crude product produced as described above
(37.36 g, 0.1 mol) and toluene (187 mL). The mixture was stirred to give
a beige/brown solution. Seeds of compound 2 (226 mg) were added and the
mixture was stirred at ambient temperature for 3 days, at 0-5° C.
for 8 hr, then at ambient temperature for another 7 days. The solution
was cooled again to 0-5° C. and stirred for 3 hr, filtered, and
the solid was rinsed with toluene. The solid was dried in the air to give
5.61 g (15% yield) of the title compound as a 97:3 mixture of anomers.

[0223]To a flask was charged the compound described in Example 2 (5.00 g,
13.3 mmol), 20% Pd(OH)2/C (1.00 g, 50% wet), isopropyl acetate (30
mL), and DMF (10 mL). The mixture was hydrogenated under 50 psig H2
at 0-5° C. for 5 hr, then at ambient temperature for 21 hr. HPLC
analysis showed the reaction to be 97% complete. The mixture was filtered
through celite and the solids were rinsed with a 3:1 isopropyl
acetate:DMF solution to provide the unprotected compound of example 2.

[0224]To Cbz-t-leu-OH dicyclohexylamine salt was added isopropyl acetate
(30 mL) and 1.0 M H2SO4 (30 mL). The mixture was agitated until
two clear phases were obtained. The aqueous phase was discarded and the
organic phase was washed with water (30 mL). The organic phase was
collected. To the organic phase was added DMF (10 mL), then
hydroxybenzotriazole (2.2 g, mmol). EDC (2.8 g) was added and the mixture
was stirred for 1 hr. To this mixture was added the above hydrogenation
solution. The mixture was stirred at ambient temperature for 8.5 hr.
Water (100 mL) was added and the mixture was stirred for 1 hr. The phases
were separated and the organic phase was washed with aqueous 0.5 M
NaHSO4, saturated aqueous sodium chloride, and water. The solution
was concentrated to dryness to give 4.04 g (62% yield) of the title
compound.

[0225]Alternatively, a 2 liter Parr pressure reactor was charged with
100.0 g (0.267 moles) a compound described in Example 2, and 10.0 g of
10% Pd/C (50% wet). The reactor was purged with nitrogen for 10 minutes.
800.0 mL of ethyl acetate, followed by 19.5 mL of trifluoroacetic acid
were then added. The reactor was then closed, pressurized to 60 psi with
hydrogen followed by venting. This cycling was repeated twice. The
reaction was stirred for 2 hours under hydrogen (60 psi). The palladium
catalyst was filtered through a pad of celite, and the filtrate was held
at 4° C. until needed for the subsequent coupling step.

[0226]To a 3 liter, 3-neck round bottom flask equipped with mechanical
stirring and a thermocouple was charged 43.3 g of 1-Hydroxybenzotriazole
(anhydrous, 0.320 moles). To this flask was added a solution of
Cbz-t-leucine (70.8 g in 430 mL of EtOAc). DMF (190 mL was charged to
this suspension, and a clear light yellow solution was achieved. To this
solution was charged 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDC, 56.3 g, 0.294 moles). A thin suspension formed, and
was stirred for 2 hours at 22° C. To this suspension was charged
the solution of the unprotected compound of example 2 (TFA salt).
Triethylamine (112 mL, 0.801 moles) was added dropwise over 30 minutes,
and the resulting suspension was stirred at 22° C. for 2 hours.
Water (400 mL) was added, and the biphasic mixture was stirred for 12
hours at 22° C. This biphasic mixture was then transferred to a
4-liter separatory funnel, and the aqueous layer was removed. The organic
layer was washed with 400 mL of saturated sodium bicarbonate solution
followed by water (2×400 mL). The ethyl acetate was distilled under
vacuum to a final volume of approximately 400 mL. To this crude solution
was charged 200 mL of heptane, followed by seeding with 1.0 g of the
compound of example 3. The cloudy suspension was then cooled to 5°
C., which resulted in the formation of a thick slurry. Additional heptane
was charged (400 mL) over a three hour period while maintaining the batch
at 5° C. The solids were isolated by vacuum filtration, rinsing
the filter cake with a 2:3 EtOAc/Heptane mixture (2×100 mL). The
solids were dried for 12 hours in a vacuum oven at 22° C., with a
nitrogen bleed (80% yield for 2 steps).

[0229]The compound described in Example 3 may be further modified by
removing the protecting group and coupling additional moieties to the
Leucine amine.

Example 4

Scheme 4 and Alternative Procedures

##STR00357##

[0231]To a 1-liter, 3-neck round bottom flask equipped with mechanical
stirring and a nitrogen inlet was charged 50.0 g of the compound of
example 2 (0.134 moles), and 10.0 g of 10% Pd/C (50% wet). The vessel was
purged with nitrogen for 10 minutes. Formic acid (500 mL) was added, and
the suspension was stirred under nitrogen for 16 hours at 22° C.
The reaction mixture was filtered through celite, and to the filtrate was
added 20.6 mL of trifluoroacetic acid. The formic acid was distilled
under vacuum, and the remaining formic acid was removed by azeotropic
distillation with toluene. The crude oil that was obtained was dissolved
in 150 mL of ethyl acetate, and methyl-tert-butyl ether (100 mL) was
charged dropwise over 2 hours to crystallize the trifluoroacetate salt.
The suspension was cooled to 5° C., and the solids were collected
by vacuum filtration, rinsing with a 3:2 EtOAc/MTBE solution (2×50
mL) to furnish the desired product as a TFA salt in 55% yield.

[0236]21.7 ml of water was added to a mixture of 100.0 g of
CBZ-prolinamide, 0.92 g of Palladium acetate, 3.47 g of Xantphos, 111.2 g
of Potassium carbonate and 2.93 g of Cetyltrimethylammonium bromide in
Toluene (1000 ml) maintaining the temperature at T=20-25° C. All
vessel chargings and additions were performed under nitrogen to
avoid/limit oxidation of the Palladium catalyst. The reaction was then
warmed to T=50-55° C. and stirred for about 2 hours. Separately,
Bromoethoxyfuranone (91.5 g) and toluene (100 ml) were charged into a
separate flask and stirred at 20-25° C. until complete dissolution
occurred. The Bromoethoxyfuranone solution was then added to the initial
reaction mixture over 3-3.5 hours at 50-55° C. and then stirred
until the reaction was completed in quantitative yield in about 1 hour.
The reaction mixture was filtered at T=50-55° C. and the solids
were rinsed with Toluene (500 ml). The filtrate was washed with water
(500 ml. The aqueous phase was discarded and the organic phase was
concentrated to approximately 500 ml at <50° C. under vacuum.
The solution was cooled to 5° C.-10° C. and 9.8 g Aluminum
triethoxide were added.

[0237]Into a separate flask 11.3 ml Acetyl chloride was added to a
solution made of 100 ml Toluene and 9.7 ml Ethanol, maintaining the
temperature at T=5-10° C. (in situ generation of anhydrous HCl),
then the mixture was stirred at T=5-10° C. for about 1 hour. The
Toluene/Ethanol/HCl solution was then added to the previous reaction
mixture over 15 minutes at T=5-10° C., then seeded with the
product and stirred at T=5-10° C. for 12 hours, at T=20-25°
C. for 48 hours, at T=5-10° C. for 12 hours. The product was
filtered at T=5-10° C. and washed with 100 ml of Toluene. The wet
material was dissolved at 70° C.-75° C.) in 1500 ml Toluene
and the solution was filtered at 75° C. through Dicalite
(filtration aid agent). The solids were rinsed with 100 ml Toluene. The
organic solution was vacuum concentrated to 500 ml. The resultant slurry
was cooled to 20-25° C. over 1 hour, stirred for 3-4 hours,
filtered and the product rinsed with 100 ml toluene. The product was
dried under vacuum at 35-40° C.

Step 2:

##STR00361##

[0239]The furanone of Step 1 100 g was charged into a stainless steel (3
it) autoclave together with 20 g of 5% Palladium on charcoal (approx. 50%
wet), followed by 800 ml of ethyl acetate and 19.5 ml of trifluoroacetic
acid. The autoclave was pressurized with hydrogen (4 bars) and the
temperature set at T=20-25° C. The hydrogenolysis was run for 2-3
hrs, periodically repressurizing to 4 bar as hydrogen uptake proceeds,
until uptake of hydrogen ceased. The catalyst was filtered off and washed
twice with 100 ml of ethyl acetate to give a solution of the deprotected
proline compound.

[0240]Separately, a solution of sulfuric acid (14.6 ml) in water (330 ml)
was added to a mixture of 119.2 g of Cbz-t-leucine dicyclohexylamine salt
and 430 ml of Ethyl acetate. The resulting solution was stirred at
T=20-25° C. for 30 minutes. The organic layer was separated,
washed twice with 500 ml of water and added to 43.3 g of
hydroxybenzotriazole. DMF (190 ml) was added to this mixture followed by
56.3 g of EDC which produced a cloudy reaction mixture from the clear
yellowish solution. The reaction was stirred at T=20-25° C. for
30-60 minutes. The solution of deprotected proline compound from the
autoclave was charged to the reaction mixture, 81.1 g of Triethylamine
was then added dropwise (over 20-30 minutes) and the resulting cloudy
mixture was stirred at T=20-25° C. for 1.5-2 hours. 400 ml of
water was added and the reaction stirred at 20-25° C. for 12
hours. The organic layer was separated and washed with 400 ml of an
aqueous sodium bicarbonate (7.5%) solution and twice with 400 ml of
water. These water washings were performed at 45-50° C. The
organic phase was concentrated to 400 ml volume at 40-45° C. 300
ml of ethyl acetate were added and the mixture concentrated to 350 ml to
remove residual water. The solution was cooled to 20-25° C. and
200 ml of N-heptane added over 1 hour at 20-25° C., and the
mixture seeded with the compound shown in Example 3 above and stirred at
T=20-25° C. for 1 hour. The resultant slurry was cooled to
T=5-10° C. and stirred for an additional hour at the same
temperature. 400 ml of N-Heptane were added over 2-3 hours at
T=5-10° C., the slurry was filtered and rinsed twice with Ethyl
acetate/N-heptane (40 ml, 60 ml respectively). The crystals were dried
under vacuum at T=35-40° C. for at least 8 hours.

Step 3:

##STR00362##

[0242]The product of step 2 (100 g), 5% Palladium on charcoal (approx. 50%
wet, 20 g) 100 ml of DMF, 600 ml of ethyl acetate and 43.1 g of Citric
acid monohydrate were charged into a stainless steel (3 it) autoclave.
The stainless steel autoclave was pressurized with hydrogen (4 bar) and
the temperature set at -2° to +2° C. The reaction was run
for 2-3 hrs periodically repressurizing to 4 bar as hydrogen uptake
proceeds. The catalyst was filtered off and washed with a mixture of 85
ml of ethyl acetate and 15 ml of DMF.

[0243]Separately, 23.5 g of N-Methylmorpholine is added to a mixture of
33.1 g of 4-Amino-chloro-benzoic acid 34.4 g of
2-Chloro-4,6-dimethoxytriazine (DMT-Cl) in 300 ml of ethyl acetate over
20-30 minutes at ambient temperature for 2-3 hours at 23-27° C. to
obtain the DMT active ester of 4-Amino-3-chlorobenzoic acid. The mixture
is cooled to 0° to +5° C. and 300 ml of purified water are
added to the solution keeping temperature in the same range. The solution
of the deprotected t-leucine product as the citrate salt is added at
0° C. to +5° C. over 30-60 minutes, the reaction mixture is
then brought to pH 6.5-7.5 by adding 30% sodium hydroxide (approx.
amount: 71 ml), and stirred 6-7 hrs at 20° to 25° C. After
completion of the reaction, the phases are separated and the organic
layer added to sodium bisulfate solution (15 g of sodium bisulfate in 235
ml of water) and stirred for 3 hrs at 20° C. to 25° C. The
phases are separated and the organic layer is washed four times with
water (150 ml each), twice with sodium bicarbonate solution (total: 20 g
of sodium bicarbonate in 400 ml of water), and once with 150 ml of water.
To the solution is added 10 g of activated charcoal and 10 g of Dicalite
and filtered and the solids washed with 100 ml of ethyl acetate. The
filtrate was distilled under vacuum to a volume of 200 ml at
<40° C. when the resultant mixture crystallizes. Ethyl acetate
(150 ml) was added to a total volume of 350 ml. N-heptane (300 ml) was
added over 2 hrs and after stirring the slurry for 3 hrs at 20° to
25°, the solid was filtered, washed with ethyl acetate/N-Heptane
(100 ml, 1:1) and dried at 60° C. under vacuum.

[0244]All of the documents cited herein are hereby incorporated herein by
reference.

[0245]While we have described a number of embodiments of this invention,
it is apparent that our basic examples may be altered to provide other
embodiments which utilize the compounds and methods of this invention.
For instance, protecting groups besides CBZ may be used to protect amines
in one or more of the synthetic steps described above. Therefore, it will
be appreciated that the scope of this invention is to be defined by the
appended claims rather than by the specific embodiments which have been
represented by way of example.